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In vivo screening characterizes chromatin factor functions during normal and malignant hematopoiesis.

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Lara-Astiaso, David 
Goñi-Salaverri, Ainhoa 
Mendieta-Esteban, Julen  ORCID logo
Del Valle, Cynthia 


Cellular differentiation requires extensive alterations in chromatin structure and function, which is elicited by the coordinated action of chromatin and transcription factors. By contrast with transcription factors, the roles of chromatin factors in differentiation have not been systematically characterized. Here, we combine bulk ex vivo and single-cell in vivo CRISPR screens to characterize the role of chromatin factor families in hematopoiesis. We uncover marked lineage specificities for 142 chromatin factors, revealing functional diversity among related chromatin factors (i.e. barrier-to-autointegration factor subcomplexes) as well as shared roles for unrelated repressive complexes that restrain excessive myeloid differentiation. Using epigenetic profiling, we identify functional interactions between lineage-determining transcription factors and several chromatin factors that explain their lineage dependencies. Studying chromatin factor functions in leukemia, we show that leukemia cells engage homeostatic chromatin factor functions to block differentiation, generating specific chromatin factor-transcription factor interactions that might be therapeutically targeted. Together, our work elucidates the lineage-determining properties of chromatin factors across normal and malignant hematopoiesis.



3101 Biochemistry and Cell Biology, 31 Biological Sciences, Cancer, Rare Diseases, Stem Cell Research - Nonembryonic - Non-Human, Genetics, Stem Cell Research, Hematology, 1.1 Normal biological development and functioning, 1 Underpinning research

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Nat Genet

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Springer Science and Business Media LLC
La Caixa (via University of Navarra) (HR20-00871)
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (886474)
European Hematology Association (EHA) (Unknown)
Cancer Research UK (25508)
Wellcome Trust (203151/A/16/Z)
Wellcome Trust (203151/Z/16/Z)
European Research Council (647685)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Kay Kendall Leukaemia Fund (KKL1440)
Cancer Research UK (A25117)
Medical Research Council (MC_PC_17230)
National Institute for Health and Care Research (IS-BRC-1215-20014)

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2023-08-29 14:30:36
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2023-05-03 00:31:15
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